Ryanodine Receptor Pore Structure and Function

Abstract

Ryanodine Receptors (RyRs) are ion channels that regulate muscle contraction by releasing calcium ions from intracellular stores into the cytoplasm. Mutations in skeletal muscle RyR (RyR1) give rise to congenital diseases such as the Central Core Disease. The absence of high-resolution structures of RyR1 has limited our understanding of channel function and disease mechanisms at the molecular level. Here, we report a structural model of the pore-forming region of RyR1 and electrophysiological studies on a Central Core Disease mutant RyR1-G4898R. Molecular dynamics simulations on the structural model show preferential localization of Ca2+ over K+ in the selectivity filter. We observe high ion binding to the residues D4899, E4900, D4938 and D4945 along the pore, which are experimentally known to be critical for channel function and selectivity. Furthermore, simulations on the mutant RyR1-D4899Q show a loss of preference to Ca2+ in the selectivity filter as seen experimentally. Electrophysiological experiments on RyR1-G4898R show constitutively open channels that conduct K+ but not Ca2+. Our simulations with G4898R likewise show a decrease in preference of Ca2+ over K+ in the selectivity filter. Together, the computational and experimental results shed light on the functioning of the RyR1 pore at an atomistic level.